Dolutegravir (DTG, GSK1349572) is an integrase inhibitor being developed for the treatment of human immunodeficiency virus (HIV)-1 infection.
Dolutegravir sodium is chemically named sodium (4R,12aS)-9-((2,4-difluorobenzyl)carbamoyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazin-7-olate and is represented by the following chemical structure:

A new crystalline or amorphous form of a compound may possess physical properties that differ from, and are advantageous over, those of other crystalline or amorphous forms. These include, packing properties such as molar volume, density and hygroscopicity; thermodynamic properties such as melting temperature, vapor pressure and solubility; kinetic properties such as dissolution rate and stability under various storage conditions; surface properties such as surface area, wettability, interfacial tension and shape; mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blend; and filtration properties. Variations in any one of these properties may affect the chemical and pharmaceutical processing of a compound as well as its bioavailability and may often render the new form advantageous for pharmaceutical and medical use.
Dolutegravir and processes for its preparation are disclosed in WO 2010/068253 and US 2009/0318421. WO 2010/068253 discloses a crystalline form of dolutegravir sodium salt characterized by the following diffraction peaks in the X-ray powder diffraction pattern at 6.4°±0.2°, 9.2°±0.2°, 13.8°±0.2°, 19.2°±0.2° and 21.8°±0.2° degrees two-theta; and the following characteristic peaks in the infrared absorption spectrum at 1641±2, 1536±2, 1503±2 and 1424±2 cm−1; and a crystalline form of dolutegravir sodium hydrate characterized by the following diffraction peaks in the X-ray powder diffraction pattern at 8.0°±0.2°, 9.3°+0.2°, 11.3°±0.2°, 16.0°±0.2° and 22.8°±0.2° degrees two-theta; and the following characteristic peaks in the infrared absorption spectrum at 1637±2, 1536±2, 1501±2 and 1422±2 cm−1. Further disclosed in WO 2010/068253 is a crystalline form of dolutegravir characterized by the following diffraction peaks in the X-ray powder diffraction pattern at 5.4°±0.2°, 10.7°±0.2°, 12.3°±0.2°, 15.2°±0.2° and 16.4°±0.2° degrees two-theta; and the following characteristic peaks in the infrared absorption spectrum at 1658±2, 1628±2, 1540±2 and 1498±2 cm−1.
There still remains an unmet need for solid state forms of dolutegravir having good physicochemical properties, desirable bioavailability, and advantageous pharmaceutical parameters.